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In a review released by the State of California Ministry of Health in 1991, the then published data from studies with animals and man were summarized and evaluated critically (Donald et al. The authors drew particular attention to the doubtful quality of some of the animal studies and pointed out that these did not provide an appropriate basis for risk assessment and the establishment of threshold values. The 'shift in foetal rib profile' in mice exposed to a toluene concentration of 400 ml/m 3, described as a teratogenic effect by Courtney et al., was not considered by Donald et al. To be a prenatal toxic effect but to be within the normal profile. Therefore a concentration of 400 ml/m 3 was given as the no observed adverse effect level for developmental toxicity (NOAEL D) for the 7-hour daily exposure of mice.

A review and critical evaluation of the available data was also published by the American Conference of Governmental Industrial Hygienists (ACGIH ). This panel of experts came to the conclusion that the published animal studies demonstrate that the embryo is not more sensitive to the effects of toluene than the dams and that therefore the American Threshold Limit Value (TLV), which had been reduced from 100 ml/m 3 to 50 ml/m 3, provided sufficient protection against adverse effects on human reproduction.

A Criteria Document for Occupational Exposure Limit Values (toluene) was produced for the Health and Safety Directorate (SEG) of the Commission of the European Communities (Jelnes ). The SEG assessment was based on the view that exposure of mice to a toluene concentration of 200 ml/m 3 produced rib profile changes and exposure of rats to 266 ml/m 3 caused reductions in foetal body weights.

On the assumption that man is as sensitive or more sensitive to the prenatal effects of toxic substances and that a safety factor of 10 is sufficient for toluene, a threshold value of 20–25 ml/m 3 for exposure of pregnant women was deduced. The SEG recommended a time-weighted average threshold level (TWA) of 20 ml/m 3 (76.4 mg/m 3) for 8-hour exposures to toluene and for brief exposure peaks a short-term exposure limit (STEL) of 50 ml/m 3 (191 mg/m 3) measured over 15 minutes. These recommendations were based on the effects of toluene in the reproductive and nervous systems. For the nervous system, the lowest observed adverse effect level (LOAEL) was established at 75 ml/m 3 (287 mg/m 3) and the no observed adverse effect level (NOAEL) at 40 ml/m 3 (150 mg/m 3). These levels were determined from data obtained after long-term human exposures which led to an increased incidence of neurasthenic symptoms such as fatigue, short-term memory disorders, lack of concentration and mood lability. Reductions in performance in psychological tests carried out after experimental exposures were also referred to in the establishment of these thresholds. The symptoms produced by chronic systemic exposure to toluene are initially not very characteristic.

In addition to the unspecific symptoms seen in acute intoxications, loss of appetite, vomiting, fatigue, nervousness and insomnia have been reported. As the intoxication progresses, the main symptoms reflect central nervous depression (gait and coordination disorders, intention tremor, etc.) and can be accompanied by changes in the electroencephalogram. They are understood to be indicative of functional disorder or damage in the cerebellum and/or corticospinal tract. After frequent intentional inhalation of large quantities of mixtures containing toluene ('sniffing'), dangerously severe renal disorders (hyperchloraemic acidosis, hypokalaemia) have been observed; they are considered to result from toluene-induced damage in the distal renal tubules. Brief skin contact with liquid toluene causes defatting and drying out of the skin; direct exposure of lung tissue by aspiration of the liquid results in unusually marked inflammation with severe sequelae such as bleeding and tissue necrosis in the lungs. The irritant effects of toluene vapour on mucous membranes are described as moderate to slight, those on the eye as slight. Evidence that long-term skin contact with liquid toluene can lead to systemic intoxication or to sensitization has not been published.

On the other hand, drying, scaling and splitting of the skin can make it more permeable for chemicals and bacteria and result in dermatitis or dermatosis. In a study of the absorption of liquid toluene through the skin (Sato and Nakayima ), much lower percutaneous absorption rates (0.17 mg/cm 2/h) were found than in earlier experiments (14–23 mg/cm 2/h) (Dutkiewicz and Tyras, ); the difference (about 100:1) appears to result from the different methods used. Although liquid toluene readily penetrates the horny layer of the skin, only about 1% to 2% of the toluene which reaches the stratum corneum can overcome this barrier and become systemically available. Most of the toluene which enters the skin leaves it again by evaporation into the air.

Exposure to toluene vapour results in even lower levels of absorption through the skin (about 0.9%) (Riihim ki and Pf ffli ). Metabolism of toluene takes place mostly in the liver in three steps: monooxygenases of the endoplasmic reticulum convert the substance to benzyl alcohol which is oxidized by cytoplasmic alcohol dehydrogenase to benzaldehyde and then by aldehyde dehydrogenase to benzoic acid (Bakke and Scheline ). Benzoic acid is conjugated with glycine by liver mitochondrial enzymes and the hippuric acid produced is excreted in the urine (Cohr and Stockholm 1979, Lauwerys, NRC, Toftgard and Gustafsson ). Phenolic metabolites ( o-cresol and p-cresol) were first found at very low levels (0.04–0.11% and 0.4–1%) in rat urine (Bakke and Scheline ) and later in human urine as well ( o-cresol up to 0.2%) (Angerer, Hasegawa et al., Pf ffli et al.

The biotransformation of toluene is shown in Figure. About 68% of the toluene absorbed in the lungs is eliminated in the urine in the form of hippuric acid (Ogata et al. It is, however, not possible to deduce the level of toluene exposure directly from the amount of hippuric acid excreted because this substance can also be produced and excreted by persons not exposed to toluene.

Likewise, after short-term exposure to low levels of toluene, neither the hippuric acid levels nor the o-cresol levels in the urine are reliable parameters of toluene exposure (Andersson et al. Studies of the interaction of toluene with other substances demonstrated that pretreatment of rats with phenobarbital markedly increased the rate of elimination of hippuric acid in the urine after intraperitoneal administration of toluene (0.43 g/kg body weight). At the same time, the narcotic effects of toluene were reduced (Ikeda and Othsuji ). Vst Cd Usb Driver Mac.

When toluene and benzene were administered simultaneously to mice, the toluene reduced the production of benzene metabolites in bone marrow and provided protection against the benzene-induced depression of Fe 59 uptake into the red blood cells (Andrews et al. Toluene suppresses the excretion of styrene metabolites in rat urine (Ikeda and Hirayama ). When toluene and trichloroethylene are administered simultaneously, reciprocal inhibition of metabolism occurs (Ikeda ). Toluene delays the excretion of n-hexane metabolites in rat urine without any apparent effects of n-hexane on the biotransformation of toluene to hippuric acid or o-cresol (Perbellini et al. Simultaneous administration of toluene and m-xylene by intraperitoneal injection has no effect on the excretion of the toluene or xylene metabolites (Ogata and Fujii, uber 1984). The data available for the distribution of toluene in tissues are almost entirely from animal studies. Initially, markedly higher toluene levels were found in the brains of rabbits and guinea pigs than in the blood (Fabre ).

In the dog, the highest levels were found in the adrenals (Gerarde ). More recently, however, the highest concentrations at all times were found in the white adipose tissue (Carlsson and Lindqvist, Koga, Ogata et al. ) followed by the kidneys, adrenals, liver and brain. Thus, the longest half-life values for toluene have been determined in adipose persons (Carlsson and Ljungquist ), a phenomenon which has also been observed in persons exposed to benzene. As recently as 1970 the literature described myelotoxic effects for toluene like those known for benzene. Although the toluene used in Germany – especially in photogravure printing – had contained less than 0.3% benzene since 1955 (B nfer ), at which time the incidence of blood disorders caused by exposure to solvents dropped abruptly (Suhr ), the usual commercial product in other countries contained up to 15% benzene (NIOSH ).

Therefore it may be concluded that the haematotoxic effects of toluene reported until the 1970s may be put down to variously high levels of contamination with benzene (Sandmeyer ). Exposure to toluene concentrations of 10000 to 30000 ml/m 3 caused sudden clouding and/or loss of consciousness (Longley et al. Acute renal failure with moderate acidosis and pathological renal parameters were also described (Reisin et al. In one of the first well documented studies (von Oettingen et al.

1942), marked and persistent sequelae such as increased nervousness, muscle weakness and insomnia were reported in persons exposed to 800 ml/m 3. Such exposures were also said to cause impairment of the olfactory nerves (Gerarde ). At concentrations of 600 ml/m 3, headaches, fatigue, nausea, dizziness and coordination and accommodation disorders were observed. In this study of von Oettingen et al. (1942) the increase in symptoms with increase in the intensity of toluene exposure is well documented (Table ).

Most of the earlier epidemiological studies and casuistics published for cases of chronic exposure to toluene involve persons handling not the pure substance but toluene containing mixtures such as solvents and thinners containing other substances such as xylene, ethylbenzene, methanol, ketones, n-hexane and, in particular, larger or smaller amounts of benzene. Only few studies reported investigations with pure toluene (. Determinations of the 51Cr-EDTA clearance in 34 employees in the photogravure printing industry who were exposed to solvents containing toluene (no analysis) at concentrations up to about 80 ml/m 3 (with occasional peaks of two to three times that concentration) revealed no impairment of glomerulus function or filtration rate (Askergren et al. In the same collective, no difference from the control group was found in the ability of the kidney to concentrate urine after 14 hours without drinking (Askergren et al.

Reports of an effect of vapours containing toluene on the menstrual cycle in women (Berka and Jelinek, Syrovadiko 1977) are inadequately documented and suggest that the toluene was contaminated with other substances. Reports of 'ischaemic cardiac disorders, high arterial blood pressure and arterial pressure raised to the limit' (Reznik and Vaisman ) resulting from exposure to mixtures containing toluene require confirmation as do observations of effects on the autonomic nervous system (Suzuki ) and the vestibular system (De Rosa et al. However, vestibular disorders have also been reported recently in 15 of 53 rotary printers (aged 23 to 60 years) exposed for an average of 11.2 years (Coscia et al. Increased hearing loss was reported in printers exposed to toluene vapour concentrations between 75 and 365 ml/m 3; the authors assumed that toluene had caused the sensory deficit (Morata et al. Some studies using neurobehavioural methods are mentioned especially (Table a) since they are important for the discussion of the lowest observed adverse effect level (LOAEL). Compared 24 printers exposed to toluene in a printing works with 18 control persons; tests took place during and after the shift on 3 consecutive days. The exposure level determined with personal samplers was 62 ml/m 3 (237 mg/m 3) averaged over the shift; measurements of the air concentrations close to the machines revealed 121 ml/m 3 (463 mg/m 3).

The persons had been exposed for an average of 13 years. Reaction times, perception time determined with a tachistoscope and the results of a visual search test were not markedly changed. Fatigue, lack of concentration, exhaustion, discord were significantly increased in the printers at the end of the shift. In the interpretation of the findings, it must also be taken into account that the printers were exposed to noise levels of about 90 dB. (1990, 1993) compared 30/24 women/men exposed to average toluene concentrations of 88/70 ml/m 3 (glue, electronic assembly) with 30/64 control persons.

The tests took place during the working week. For persons exposed to higher concentrations, performance was significantly poorer in a visual search test, visual reproduction test, verbal memory test and manual dexterity test. In 6 of 8 tests the performance decreased with increased average workplace concentration. Both the duration of exposure and the level of occupational training (confounding factor affecting performance in psychological tests) were taken into account. Oerbaek and Nise studied 30 printers exposed on average for 29 years in parallel with 72 'healthy men' as control group. Current toluene concentrations were determined as 11 ml/m 3 and 42 ml/m 3; in previous years the concentrations had been considerably higher. Tests carried out on Monday mornings revealed performance deficits in the exposed persons.

However, no correlation with a cumulative exposure index or with the current average exposure was found. Fatigue, short-term memory problems, concentration difficulties and mood swings were more frequent in the printers.